Year: 2017
Type: article
Abstract: Significance Histone deacetylase 6 (HDAC6) is a zinc metalloenzyme that serves as the tubulin deacetylase in the cell cytosol. Inhibition of tubulin deacetylase activity leads to suppression of microtubule dynamics, causing cell cycle arrest and apoptosis, which is a validated strategy for cancer chemotherapy. Selective inhibition of HDAC6 is clinically preferable, since unwanted inhibition of other HDAC isozymes can lead to undesirable off-target effects. Here, X-ray crystal structures of HDAC6-inhibitor complexes reveal molecular features responsible for the isozyme selectivity measured in inhibition assays, including an unusual monodentate hydroxamate-Zn 2+ coordination mode as well as intermolecular interactions of bulky inhibitor substituents. These observations will inform the design of HDAC6-selective inhibitors with improved properties.
Institutions: University of Pennsylvania, Columbia University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: U.S. Department of Energy, Celgene, National Institutes of Health, Office of Science, National Institute of General Medical Sciences, National Center for Research Resources, Basic Energy Sciences, Biological and Environmental Research, Argonne National Laboratory, SLAC National Accelerator Laboratory
Awards: G102163711, G107546177, G1229526393, G1286236842, G1286251239, G1313983767, G1337544421, G1451874870, G1664757510, G1804828992, G1831385526, G2164036156, G223002938, G2287611682, G2371548206, G2539837713, G262532246, G262962599, G2638771445, G2857925935, G303061748, G30714459, G3075337988, G3083819904, G315621713, Pixel Array Detector for X-ray Crystallography, G3407338877, G3488436650, G3629260272, G382641700, G409777406, G419881185, G4235786860, G426311843, G4269941704, G4280418065, G42916606, G4501827968, G4581610328, G495301720, G498139845, G5201631574, G5387317844, G5570207115, G5607048534, G618388848, G650090426, G6550344761, G6848031779, G6918803902, G7283024673, G7538797784, G7583137537, G7787287669, G8382000481, A Synchrotron Radiation Structural Biology Resource, NE-CAT Center for Advanced Macromolecular Crystallography, G8925327636, Predoctoral Training at the Chemistry-Biology Interface, Structure and Function of Metalloenzymes, G911061179, G969889393, G993149817
OpenAlex ID: W2773548225